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Case ReportPrimary Neuroendocrine Tumor in Brain

Ryota Tamura, Yoshiaki Kuroshima, and Yoshiki Nakamura

Department of Neurosurgery, Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo 152-8902, Japan

Correspondence should be addressed to Ryota Tamura; [email protected]

Received 27 September 2014; Accepted 11 November 2014; Published 20 November 2014

Academic Editor: N. Scott Litofsky

Copyright © 2014 Ryota Tamura et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The incidence of brain metastases for neuroendocrine tumor (NET) is reportedly 1.5∼5%, and the origin is usually pulmonary.A 77-year-old man presented to our hospital with headache and disturbance of specific skilled motor activities. Computedtomography (CT) showed a massive neoplastic lesion originating in the left temporal and parietal lobes that caused amass edematous effect. Grossly, total resection of the tumor was achieved. Histological examination revealed much nuclearatypia and mitotic figures. Staining for CD56, chromogranin A, and synaptophysin was positive, indicating NET. The MIB-1 index was 37%. Histopathologically, the tumor was diagnosed as NET. After surgery, gastroscopy and colonoscopy wereperformed, but the origin was not seen. After discharge, CT and FDG-PET (fluoro-2-deoxy-d-glucose positron emissiontomography) were performed every 3 months. Two years later we have not determined the origin of the tumor. It ispossible that the brain is the primary site of this NET. To our knowledge, this is the first reported case of this phe-nomenon.

1. Introduction

Neuroendocrine tumors (NETs) are neoplasms derived fromnerve and endocrine cells. NETs have the ability to producehormones and have similarities with nerve cells, such ascytoplasmic granules and exocytotic machinery. NETs werecalled “carcinoid” 100 years ago and were considered benignneoplasms. Currently they are considered to be malignant,and the WHO histopathological classification eliminated the“carcinoid” label in 2000. In the WHO classification of 2010,NETs were defined as neuroendocrine neoplasms and wereclassified as NET G1, NET G2, NEC (large cell or small celltype), mixed adenoneuroendocrine carcinoma (MANEC),hyperplastic, and preneoplastic lesions, by theKi-67 index [1–4]. NETs are increasing and are therefore attracting interestand attention. Generally, the majority of metastases occur inthe liver, lungs, and bone. Other sites are rarer, and brainmetastases are very rare. Here we present a case report ofa probable primary brain NET. To our knowledge, this isthe first reported case of a primary NET arising in thatanatomical location.

2. Case Presentation

A 77-year-old man presented with headache and disturbanceof skilled motor activities. The past medical history includedhypertension, diabetes, and chronic idiopathic pericardialeffusion. On physical examination, the Glasgow Coma Scale(GCS) score was 14 (E4V4M6), and finger agnosia andleft-right disorientation were noted, like in the Gerstmannsyndrome. Blood and CSF analyses were normal. Levels oftumor markers, including CEA, CA19-9, NSE, AFP, and IL-2R, were normal. Head computed tomography (CT) showeda massive neoplastic lesion of 6.6 cm in diameter originatingin the left temporal and parietal lobes that caused a massedematous effect. That lesion included a high-density areain the dorsal aspect that indicated hemorrhage (Figure 1(a)).Enhanced CT showed ring enhancement (Figure 1(b)). Headmagnetic resonance imaging (MRI) showed a subcorticallesion that contained a cyst and hemorrhage. The centralportion was low on T1-weighted imaging (T1WI) and highon T2-weighted imaging (T2WI) (Figures 2(a) and 2(b)).Thecyst in the tumorwas not enhanced, but other sites were inho-mogeneously enhanced (Figure 2(c)). Diffusion-weighted

Hindawi Publishing CorporationCase Reports in Neurological MedicineVolume 2014, Article ID 295253, 6 pageshttp://dx.doi.org/10.1155/2014/295253

2 Case Reports in Neurological Medicine

(a) (b)

(c) (d)

Figure 1: (a) Axial nonenhanced CT scan on admission shows a sharply marginated mass of 6.6 cm in diameter in the left temporal andparietal lobes and compressing the surrounding parenchyma. The left lateral cerebral ventricle is compressed. The lesion had a high-densityregion in the dorsal aspect indicating hemorrhage. (b) Axial enhanced CT image shows a massive lesion like a cyst with enhancement. (c)Digital subtraction angiography (DSA) of the frontal view shows tumor staining via the middle cerebral artery. (d) DSA of the lateral viewshows tumor staining and no arteriovenous shunts.

image (DWI) shows low-intensity area (Figure 2(d)). Therewere no other neoplastic lesions noted on whole-body CTscanning. Angiographic examination showed tumor stain-ing via the left middle cerebral artery, and no AV shuntswere seen (Figures 1(c) and 1(d)). Neuronavigation guidedtumor removal was performed after oral administration of5-aminolevulinic acid (5-ALA) on admission Day 11. Thetumor had recruited new blood vessels, like red veins, onthe brain surface, and the tumor bled easily (Figure 3(a)).We observed old hemorrhage and yellowish fluid in thecystand completely resected the lesion by gyrectomy (Figures3(b), 3(c), and 3(d)). After that, we resected using 5-ALAfluorescence as a rider. Histopathologically, the tumor wasfilled with necrosis, and a large number of cells with nuclearatypia were recognized around the vessels. The atypical cellswere characterized by their oval shaped nuclei, high N/Cratio, andmarkedly increased chromatin.Therewas a portion

where the disposition appeared to be flowing and enlargednuclear bodies were not seen (Figures 4(a) and 4(b)). Onimmunostaining, glial fibrillary acidic protein (GFAP) wasnegative, and cytokeratin-pan AE1/AE3 was positive. Forthe differential diagnosis, glioblastoma was ruled out, andwe considered metastasis of carcinoma. Cytokeratin 7 waspositive, cytokeratin 20 was negative, and epithelial mem-brane antigen (EMA) was positive. Lymphocytic markerswere negative. As for endocrine markers, chromogranin A,CD56, and synaptophysin were slightly positive (Figures 4(c)and 4(d)). Also, thyroid transcription factor 1 (TTF-1) waspositive on most tumor cells, and surfactant apoprotein wasnegative. However, thyroglobulin and calcitonin indicatingthyroid cancer were negative. CD99 was negative, so primi-tive neuroectodermal tumor (PNET)was interpreted as nega-tive. Both 34𝛽E12 and E-cadherin were negative. Consideringthe pathology and immunostaining results, a high-grade

Case Reports in Neurological Medicine 3

(a) (b)

(c) (d)

Figure 2: (a) Axial plain T1-weightedMR image shows homogeneous low-intensity area in the left temporal and parietal lobes. (b) Axial plainT2-weightedMR image shows a high-intensity area that indicates hemorrhage, a cyst, andmarked peritumoral edema. (c) Diffusion-weightedimage (DWI) shows low-intensity area not indicative of abscess. (d) Axial enhanced T1-weighted MR image shows ring enhancement.

endocrine carcinoma was thought feasible. Grossly, totalresection of the tumor was achieved; this was confirmed bypostoperative enhanced CT. The mass effect had decreased,and CT showed a small amount of hemorrhage caused bythe operation. After surgery, imaging by gastroscopy andcolonoscopy was performed, but a tumor origin was notdetected. Also, ultrasonography could not point out thethyroid lesions. Postoperative whole brain radiation therapy(30Gy) was performed from Day 26 to Day 42. The patienthad just a little motor aphasia after surgery and was dis-charged on Day 57. After discharge from the hospital, CTand FDG-PET (fluoro-2-deoxy-d-glucose positron emissiontomography) were performed every 3 months, but a tumororigin outside the brain was not identified. On Day 270, anMRI revealed a small local recurrencewith ring enhancementin the left parietal lobe near the operative site. Therefore asecond surgical procedure was performed with neuronaviga-tion and use of 5-ALA. We resected broadly, as is done fora gyrectomy. But on Day 570, MRI again revealed the small

local recurrence, so gamma knife therapy was performed.From then on, until the writing of this paper (Day 720), thepatient has remained free from relapse.

3. Discussion

Generally, the majority of NET metastases occur in the liver,lungs, and bone, and involvement of other sites is much rarer.NETs are considered to be the origin of brain metastases in1.5∼5% of all patients with brainmetastases, and in 45–71% ofthese patients, the primary tumor was located in the bronchior lungs. If brain metastases are present, lymph node metas-tases are found in 75% and liver metastases are found in 50%of these patients [5–8]. Primary unknown NET representsjust 13% of these tumors. It is difficult to detect the primaryfocus, especially for functional NETs, because patients havespecific symptomswhen the tumor size is small. Somatostatinreceptor scintigraphy (SRS) is useful to detect the primaryfocus, especially for NET G1 and NET G2, whereas PET


(a) (b)

(c) (d)

Figure 3: (a) The brain surface was yellow and had abnormal neovascularization. (b) The tumor bled easily and had some cysts and areas ofold hemorrhage. (c)The tumor was resected totally in a procedure similar to gyrectomy. 5-ALA was used to assess resection. (d) Exenteratedspecimen was yellowish and 5 cm in diameter.

is more sensitive. The most widely used tracer is F18-deoxyglucose (FDG), but well-differentiated NETs do notuptake the FDG very well; therefore, 68Ga-DOTA-TOC PETcould be better for detecting pulmonary NETs [9]. Somato-statin receptor imaging, by 111In-pentetreotide scintigraphyor PET with 68Ga-DOTA-TOC PET, frequently identifieslesions that are not visible on other radiographic images.Currently, somatostatin receptor scintigraphy with 111In-pentetreotide is frequently available technique to determinesomatostatin receptor expression. In the future, because ofits higher sensitivity, 68Ga-DOTA-TOC PET is expected toreplace somatostatin receptor scintigraphy. However, 68Ga-DOTA-TOCPET is not available in any place. So FDG-PET ismore easy to be performed. FDP-PET is usually sufficient fordetection of the tumor if the patient has a long-term follow-up even if the tumor is not high-grade NET.

To our knowledge, there is only one previous reportof a possible primary brain NET lesion [10]. The patient,a 35-year-old man, had one larger lesion with mixed solid

and cystic components located in the left basal ganglia andthalamus and a second cystic lesion located deep in theright parietal lobe.The lesions had similar ring enhancement.But this patient had multiple lesions, so the conclusion waspossiblemetastases. Our case involved a single lesion and hadonly local recurrence during a prolonged course. FDP-PETcould not detect an origin outside the brain, and tumormarkers of possible origin like thyroid cancer were negative.TTF-1 that indicates lung or thyroid cancer was certainlypositive. However, it is also said that specificity of TTF-1 isnot so high. In our case, as I described in case presentation,thyroglobulin and calcitonin indicating thyroid cancer werenegative. Lung cancer is usually detected within the long-term follow-up period with CT and PET, but it was notdetected in this case. This is a rare clinical course, and wecould not deny the possibility that brain was the primarysite. So there is the possibility that brain was the primarysite of this NET. To our knowledge, this is the first reportedcase of this phenomenon.There are some other brain tumors

Case Reports in Neurological Medicine 5

(a) (b)

(c) (d)

Figure 4: (a) Photomicrograph showing the tumor filled with necrosis. (H&E stain, original magnification ×20. Bar: 1000 𝜇m.) MIB-1 index,37%. (b) Photomicrograph showed a large number of cells with nuclear atypia around the vessels. (H&E stain, original magnification ×100.Bar: 100𝜇m.) (c) Chromogranin stain is positive. (Original magnification ×200. Bar: 100 𝜇m.) (d) Synaptophysin stain is positive. (Originalmagnification ×200. Bar: 100 𝜇m.)

that have an epithelial-like pattern, such as ependymoma,pineal tumor, and choroid plexus adenoma. However, thereare no epithelial cells in the brain and NET from a centralnerve origin is unlikely. Central nerves become neurocanalsin the early stages of development, so presence of ectopicepithelial cells is unlikely; however, it seems there may besome exceptions to that general rule. Making primary site ofbrain as new concept is so important learning point.

4. ConclusionsThis is the first reported case of a primary NET arising inbrain.

It is possible that aberrant ectopic epithelial cells arefound in the brain.

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper.

References

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[2] K. Oberg and D. Castellano, “Current knowledge on diagnosisand staging of neuroendocrine tumors,” Cancer and MetastasisReviews, vol. 30, no. 1, pp. 3–7, 2011.

[3] T.-C. Liu, N. Hamilton,W. Hawkins, F. Gao, and D. Cao, “Com-parison of WHO classifications (2004, 2010), the Hochwaldgrading system, and AJCC and ENETS staging systems inpredicting prognosis in locoregional well-differentiated pancre-atic neuroendocrine tumors,”The American Journal of SurgicalPathology, vol. 37, no. 6, pp. 853–859, 2013.

[4] T. Yamaguchi, T. Fujimori, S. Tomita et al., “Clinical validationof the gastrointestinal NET grading system: Ki67 index criteriaof the WHO 2010 classification is appropriate to predict metas-tasis or recurrence,”Diagnostic Pathology, vol. 8, no. 1, article 65,2013.


[5] F.Maiuri, P. Cappabianca,M. del Basso de Caro, and F. Esposito,“Single brain metastases of carcinoid tumors,” Journal of Neuro-Oncology, vol. 66, no. 3, pp. 327–332, 2004.

[6] R. A. Patchell and J. B. Posner, “Neurologic complications ofcarcinoid,” Neurology, vol. 36, no. 6, pp. 745–749, 1986.

[7] M. Pavel, A. Grossman, R. Arnold et al., “ENETS consensusguidelines for the management of brain, cardiac and ovarianmetastases from neuroendocrine tumors,”Neuroendocrinology,vol. 91, no. 4, pp. 326–332, 2010.

[8] J. C. Yao, M. Hassan, A. Phan et al., “One hundred yearsafter “carcinoid”: epidemiology of and prognostic factors forneuroendocrine tumors in 35,825 cases in the United States,”Journal of Clinical Oncology, vol. 26, no. 18, pp. 3063–3072, 2008.

[9] M. Kujas, T. Faillot, B. Roncier, M. Catala, and J. Poirier,“Astroblastomas revisited. Report of two cases with immuno-cytochemical and electron microscopic study. Histogeneticconsiderations,” Neuropathology and Applied Neurobiology, vol.26, no. 3, pp. 295–298, 2000.

[10] F. M. Brehar, R. M. Gorgan, and A. Neacsu, “Brain metastasesof neuroendocrine tumor with unknown primary location: casereport,” Romanian Neurosurgery, vol. 20, no. 2, pp. 159–165,2013.

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